Molecular and Cellular Biology, August 1999, p. 5504-5511, Vol. 19, No. 8
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Histone Deacetylase 1 Can Repress Transcription by Binding
to Sp1
Angelika
Doetzlhofer,1
Hans
Rotheneder,1
Gerda
Lagger,1
Manfred
Koranda,1
Vladislav
Kurtev,1
Gerald
Brosch,2
Erhard
Wintersberger,1 and
Christian
Seiser1,*
Institute of Molecular Biology, Vienna
Biocenter, University of Vienna, Vienna,1 and
Institute of Microbiology, University of Innsbruck, Medical
School, Innsbruck,2 Austria
Received 6 November 1998/Returned for modification 17 December
1998/Accepted 27 April 1999
 |
ABSTRACT |
The members of the Sp1 transcription factor family can act as both
negative and positive regulators of gene expression. Here we show that
Sp1 can be a target for histone deacetylase 1 (HDAC1)-mediated transcriptional repression. The histone deacetylase inhibitor trichostatin A activates the chromosomally integrated murine thymidine kinase promoter in an Sp1-dependent manner. Coimmunoprecipitation experiments with Swiss 3T3 fibroblasts and 293 cells demonstrate that
Sp1 and HDAC1 can be part of the same complex. The interaction between
Sp1 and HDAC1 is direct and requires the carboxy-terminal domain of
Sp1. Previously we have shown that the C terminus of Sp1 is necessary
for the interaction with the transcription factor E2F1 (J. Karlseder,
H. Rotheneder, and E. Wintersberger, Mol. Cell. Biol. 16:1659-1667,
1996). Coexpression of E2F1 interferes with HDAC1 binding to Sp1 and
abolishes Sp1-mediated transcriptional repression. Our results indicate
that one component of Sp1-dependent gene regulation involves
competition between the transcriptional repressor HDAC1 and the
transactivating factor E2F1.
| |
INTRODUCTION |
The chromatin of eukaryotic cells is
organized in nucleosomes. This organization allows the efficient
packaging of chromosomal DNA into the nucleus but limits the access of
high-molecular-weight protein complexes of the
transcription machinery. At least two different mechanisms enable
the eukaryotic cell to relieve nucleosomal repression: the
chromatin-remodeling complexes (reviewed in references 55 and 57) and reversible histone
acetylation. Two recent reports indicate a direct link between these
two activities (60, 67). Posttranslational acetylation on
conserved lysine residues within the N-terminal regions of nucleosomal
histones is assumed to lead to a reduced attraction between chromosomal
DNA and histone tails and changed interactions with neighboring
nucleosomes or other nonhistone proteins. The resulting local chromatin
decondensation increases the accessibility of particular DNA regions
for RNA polymerase complexes. Consistent with this idea,
transcriptionally active chromatin correlates with histone
hyperacetylation (reviewed in references 18, 30, 47, 49,
61, and 62). This model predicts that
histone acetyltransferases would promote transcription, while histone
deacetylases (HDACs) should act as repressors. In accordance with this
model, several transcriptional adapters and coactivators, such as GCN5
(8, 31), p300/CBP (4, 46), TAFII250
(40), SRC-1 (54), and ACTR (10), have
been classified as histone acetyltransferases. Five HDACs have been
identified in mammalian cells (12, 14, 56, 58, 63, 64).
Three of them, HDAC1, HDAC2, and HDAC3, have significant homology to yeast Rpd3 (44, 50, 59). HDAC4 and HDAC5 belong to the
histone deacetylase A (HDA) family (9, 58). HDAC1 and HDAC2
are found in high-molecular-weight complexes associated with adapter
proteins like SIN3, SAP18, and SAP30 and nuclear corepressors like
N-CoR, SMRT, and SUN-CoR (2, 24, 32, 42, 65, 66). Recently it was demonstrated that several mammalian transcription factors, such
as Mad (21, 24, 32, 52), YY1 (64),
hormone-dependent nuclear receptors (24, 42), MeCP2
(26, 43), CBF (27), retinoblastoma protein (Rb)
(7, 38, 39), and related pocket proteins (16),
can repress transcription by recruiting HDACs to specific promoters. In
addition, the aberrant recruitment of HDACs by PLZF, PML, and ETO
fusion proteins can interfere with the differentiation of hematopoietic
precursor cells in acute promyelocytic leukemia (13, 17, 19,
35).
In this study we investigated the potential function of HDACs as
transcriptional repressors during the growth arrest of mammalian cells.
Using the S-phase-specific mouse thymidine kinase (TK) promoter as a
model system, we show that HDAC1 can mediate transcriptional repression
via the Sp1 binding site. HDAC1 is associated with Sp1 and binds
directly to the C-terminal part of Sp1 that was previously identified
as interacting domain for E2F1 (28). Sp1 and E2F1 cooperate
in the activation of S-phase-specific promoters (28, 36).
Here we show that E2F1 but not E2F4 can compete with HDAC1 binding to
Sp1, thereby relieving HDAC1-mediated repression of the TK promoter.
Finally, we present a model of how transcription factors and
histone-modifying enzymes could regulate the activity of specific
promoters at the G1/S boundary of the cell cycle.
| |
MATERIALS AND METHODS |
Cell culture and transfection.
Swiss 3T3 fibroblasts and
human 293 cells were grown in Dulbecco's modified Eagle's medium
supplemented with antibiotics and 10% fetal calf serum. Swiss 3T3
cells were stably transfected by Polybrene-assisted gene transfer
(3). Briefly, 3T3 fibroblasts were seeded at 106
cells per 100-mm-diameter dish. The culture medium was replaced with 4 ml of a cocktail consisting of 5 µg of Polybrene per ml and 50 ng of
plasmid DNA per ml in fresh medium. After 16 to 20 h, the mixture
was removed and the cells were treated with 15% dimethyl sulfoxide
(DMSO) in growth medium for 4 to 5 min. The cells were rinsed twice
with growth medium and returned to the incubator for 24 h before
Geneticin-containing medium was added. Geneticin-resistant clones were
pooled for further investigations. The results described in this study
are representative of those from experiments with both single clones
and mixed populations. Transient transfection of 293 cells was carried
out by calcium phosphate coprecipitation as described previously
(28). Swiss 3T3 cells were growth arrested by reducing the
serum concentration in the culture medium to 0.2% for 72 h and
restimulated to enter the cell cycle with fresh medium containing 20%
fetal calf serum. Trichostatin A (TSA) (Wako) was dissolved in DMSO and
added to the culture medium at a final concentration of 80 to 100 ng/ml. A corresponding volume of DMSO was added to the control cells. Growth arrest and stimulation were routinely controlled by
fluorescence-activated cell sorter analysis with a Partec PAS-II sorter.
Coimmunoprecipitations.
Whole-cell extracts were prepared as
described previously (1), and equal amounts (500 µg) were
incubated in 200 µl of extraction buffer (20 mM Tris-HCl [pH 8.0],
100 mM NaCl, 1 mM EDTA, 0.5% Nonidet P-40, 1 mM phenylmethylsulfonyl
fluoride, 2 mM dithiothreitol, Boehringer Complete Protease Inhibitor
Cocktail) with 3 to 5 µl of the respective antibody for 1 h at
4°C. After addition of 20 µl of a protein A-Sepharose bead
suspension (10%, vol/vol; Pharmacia), the mixture was further
incubated with gentle shaking for 12 h at 4°C. After three
washes with extraction buffer, the beads were resuspended in 50 µl of
extraction buffer, and 30-µl aliquots were examined for protein
expression on Western blots. The remaining 20 µl was assayed for HDAC
activity (see below).
The following antibodies were used in this study. Rb was
immunoprecipitated and detected with C15 (Santa Cruz). Sp1 was
immunoprecipitated and detected with a polyclonal rabbit antiserum
raised against the full-length protein, generously provided by G. Suske
(20). HDAC1 was immunoprecipitated and visualized on Western
blots with a polyclonal rabbit antibody raised against a recombinant
mouse HDAC1 polypeptide (5) (Upstate Biotechnology). Sin3A
and Sin3B were precipitated with AK-11 (Santa Cruz) and AK-12 (Santa
Cruz), respectively. Hemagglutinin (HA)-tagged and Myc-tagged proteins were immunoprecipitated and detected with the monoclonal sera for the
HA epitope (12CA5 and 16B12) and for the Myc epitope (9E10) (15). Glutathione S-transferase (GST) fusion
proteins were detected with a polyclonal rabbit serum that recognizes
specifically the GST epitope (generously provided by K. Kuchler,
Institute of Molecular Genetics, University of Vienna).
HDAC assays and luciferase reporter assays.
HDAC assays were
done as described previously (5, 33). To measure enzymatic
HDAC activity, equal amounts (10 µg of whole-cell extract) of protein
or 20 µl of immunoprecipitated proteins was incubated with 10 µl of
[3H]acetate-labeled chicken erythrocyte histones in a
total volume of 50 µl for 1 h at 30°C. The reaction was
stopped by addition of 36 µl of 1 N HCl-0.4 M acetate and 800 µl
of ethyl acetate. After centrifugation at 8,400 × g
for 5 min, the radioactivity in a 600-µl aliquot of the organic phase
was counted in 3 ml of liquid scintillation cocktail. For luciferase
reporter assays, cells were grown in six-well plates and lysed 48 h after transfection in luciferase lysis buffer (100 mM K-phosphate
[pH 7.8], 0.2% Triton X-100). Luciferase activity and
-galactosidase activity (as a control for transfection efficiency)
were assayed in parallel by using the Dual Light Chemoluminiscent
Reporter Gene Assay System (TROPIX, Bedford, Mass.). An aliquot of each
extract was analyzed on Western blots for the expression levels of
cotransfected proteins.
GST pull-down assays.
Recombinant proteins were expressed in
and purified from Escherichia coli BL21 as described
previously (28). Beads coated with GST fusion proteins (2 µg) were incubated in binding buffer (20 mM HEPES [pH 7.9], 1 mM
MgCl2, 40 mM KCl, 0.1 mM EDTA, 0.1% Nonidet P-40) with 500 µg of whole-cell extract, radiochemical amounts of in
vitro-translated proteins, or 2 footprint units (FPU) of purified human
Sp1 (Promega) for 2 h at 4°C. After three washes with GST wash
buffer (100 mM KCl, 20 mM Tris-HCl [pH 8.0], 5 mM MgCl2,
0.1 mM EDTA, 10% glycerol, 0.5% Nonidet P-40, 0.5 mM dithiothreitol),
bound proteins were eluted by boiling in sodium dodecyl
sulfate-polyacrylamide gel electrophoresis loading buffer, resolved by
electrophoresis, and visualized by Western blotting. In vitro
expression of radiolabeled proteins was performed in reticulocyte
extracts (Quick Coupled Transcription/Translation system; Promega) in
the presence of [35S]methionine. Labeled proteins were
resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis,
and gels were dried and exposed to X-ray films at 
70°C. The signals
of labeled proteins were quantified with a Molecular Dynamics Storm 840 Scanner.
Plasmids.
To generate the selectable luciferase reporter
plasmid pGL2neo, the neomycin resistance gene from pSV2neo (Clontech)
was inserted into the BamHI site of the pGL2 vector
(Promega). The EcoRI/NheI fragment encompassing
the murine TK promoter was cloned into the pGL2neo vector (pTK-luc).
To obtain pTK-Sp1mut-luc and pTK-E2Fmut-luc, the corresponding
EcoRI/NheI fragments were excised from
pTKEcoSp1mut-ATG-CAT and pTKEcoE2Fmut-ATG-CAT (28)
and cloned into pGL2neo. To clone pCIneoHDAC1, the
EcoRI/PstI mouse HDAC1 cDNA fragment
(5) containing the entire open reading frame was cloned into
Bluescript pKS. The mammalian expression plasmid pCIneoHDAC1myc
encoding an epitope-tagged version of HDAC1 was described previously
(5). The insert was excised by EcoRI and
NotI digestion and ligated into pCIneo. The parental plasmid
pCIneo-HA was created by inserting a double-stranded oligodeoxynucleotide encoding the peptide MAYPYDVPDYA into the XhoI-cut vector pCIneo (Promega). To clone pCIneo-HA-Sp1,
the Sp1 cDNA was inserted into XbaI-cut pCIneo-HA.
Expression vectors encoding HA-Sp1 mutants were generated by cutting
pCIneo-HA-Sp1 with PpuMI and SmaI
[pCIneo-HA-Sp1(1-293)], with SmaI and BamHI (partially) [pCIneo-HA-Sp1(1-621)], with SmaI and
XmnI (partially) [pCIneo-HA-Sp1(1-668)], or with
BamHI [pCIneo-HA-Sp1(622-788)] and religating the plasmid.
The GST-Sp1 constructs have been described previously (28).
GST-HDAC1 was generated by inserting the murine HDAC1-coding sequence
into BamHI- and EcoRI-cut pGEX-2TK. The reporter
plasmids pSp1-luc and pmtSp1-luc were kindly provided by H. Nomura
(53).
| |
RESULTS |
TSA-dependent induction of the murine TK promoter in
G0-phase cells is linked to the Sp1 site.
We have
previously shown that the mouse TK gene is transcriptionally regulated
by E2F and Sp1 (28). Binding of both proteins is essential
for activation of the TK promoter during the S phase of the cell cycle.
The interaction of the DNA-binding proteins is direct (28)
and was shown to be strongly enhanced during the late G1
phase of the cell cycle (36). Given that the TK promoter is
inactive in G0-phase cells, we investigated whether HDAC
activity is necessary for this repression. Figure
1 shows that a stably integrated TK
luciferase reporter gene can be activated in serum-starved Swiss 3T3
cells by the HDAC inhibitor TSA. The activity of the TK promoter was
ninefold induced by TSA, compared to a sevenfold stimulation by 20%
fetal calf serum. Interestingly, the presence of an intact Sp1 binding
site was required for this effect, while the binding of E2F was
dispensable for the activating effect of TSA. Both mutated promoters
show significantly lower affinity than the wild-type promoter due to
loss of the cooperativity between the two transcription factors
(28). The promoter construct with a mutated Sp1 site and an
intact E2F binding site showed a less-than-twofold response to TSA but
was still responsive to serum. Mutation of the E2F site, on the other
hand, led to nearly complete loss of the growth factor response but had
no effect on the inducibility by the HDAC inhibitor. A reporter
construct with mutations in both binding sites was not responsive to
TSA (13a).
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FIG. 1.
Sp1 binding sites can mediate transcriptional activation
by TSA. (A) The Sp1 binding site is required for activation of the
murine TK promoter by TSA in resting Swiss 3T3 cells. Serum-deprived
cells containing the chromosomally integrated luciferase reporter genes
pTK-luc, pTK-E2Fmut-luc, and pTK-Sp1mut-luc were incubated for 20 h either with TSA (80 ng/ml) or fresh medium supplemented with 20%
fetal calf serum. Data are means and standard deviations from three
independent experiments. rel., relative. (B) 293 cells were transiently
transfected with a reporter plasmid containing three Sp1 consensus
sites (pSp1-luc) or a construct bearing three mutated Sp1 sites
(pmtSp1-luc) together with the control vector pCMVGal. In each
transfection experiment half of the cells were treated with TSA (100 ng/ml) for 20 h. Luciferase activities of untreated cells (white
bars) and TSA-treated cells (gray bars) are depicted relative to the
respective -galactosidase activities. (C) pSp1-luc was transfected
together with pCIneo, pCIneoHA-Sp1wt, and pCIneoHA-Sp1wt in combination
with increasing amounts of pCIneomyc-HDAC1 (0.25, 0.75, and 1.25 µg).
Luciferase activities are depicted relative to the respective
-galactosidase activities. Expression levels of epitope-tagged Sp1
and HDAC1 were analyzed on Western blots with HA-specific and
Myc-specific antibodies.
|
|
To demonstrate that the TSA effect is independent of the presence of
other transcription factor binding sites, we examinedReversible acetylation of histones and corresponding changes
of chromatin structure are substantial elements of gene
regulation. Many histone acetyltransferases and HDACs are
capable of interacting with constituents of the transcription
apparatus, thereby causing promoter-specific alterations of
chromatin. We have been interested in the growth control of gene
expression, with the S-phase-specific TK gene as a model.
Promoters of growth-regulated genes often carry binding sites for Sp1
and E2F. Depending on the promoter, members of the E2F family can
function in one of two ways. First, together with their interacting
pocket protein (Rb, p107, or p130), they can inhibit promoter activity;
phosphorylation of the pocket protein then causes rapid dissociation of
the pocket protein-E2F complexes. This is likely the case for E2F4 and
E2F5 and the corresonding pocket proteins p130 and p107. The second
type of regulation involves E2F1, -2, or -3. These E2F proteins,
together with a pocket protein, can inhibit transcription, but upon
release of the phosphorylated pocket protein they can also act as
positive transcription factors. The murine TK promoter and the promoter
of the dihydrofolate reductase (DHFR) gene are probably regulated in
this way. In both cases, there appears to be a strong interaction
between Sp transcription factors and E2F in which Sp1, Sp3 and E2F1,
-2, or -3 are implicated. Mutation of the binding site for E2F in this
case not only leads to deregulation of the promoter but causes nearly
complete inactivation. Down-regulation of promoters by the E2F-pocket
protein complex is thought to entail deacetylation of histones via
pocket protein-HDAC interaction. In contrast to E2F, Sp1 was so far
seen primarily as a positive transcription factor. Our study
demonstrates that Sp1 can also be targeted by the repressor HDAC1.
Binding sites for Sp1 are very common in many promoters, and several
Sp1 proteins can bind to these GC-rich motifs, with various
consequences. Of these proteins, Sp1 and Sp3 are the most prevalent
ones found in mammalian cells. In fact, we observed that Sp3 binds
HDAC1 just like Sp1 (49a). The interaction of Sp1 with HDAC1
requires the part of Sp1 which was previously shown to be implicated in the binding to E2F. Accordingly, HDAC1 was found to compete with E2F1
for binding to Sp1. This competition may play an important role in the
regulation of promoters, which present closely spaced binding sites for
Sp1 and E2F.
A model for the growth control of the murine TK promoter which
incorporates the currently known interactions is shown in Fig. 8. During growth arrest, the E2F complex
carries p130 most likely bound to E2F4. As E2F4 lacks the sequence
required for interaction with Sp1, the nearby Sp1 is able to bind
HDAC1. Thus, both Sp1 and p130 recruit HDAC1, thereby causing full
inactivation of the promoter. The fact that a mutant TK promoter
lacking the Sp1 binding site is insensitive to TSA is possibly due to
the absence of E2F1 in resting fibroblasts. E2F1 was recently shown to
be necessary for the effect of TSA on promoters repressed by the
Rb-HDAC1 complex (39). After growth stimulation, p130 is
phosphorylated, the E2F pocket protein complex dissociates, and E2F4
relocalizes to the cytoplasm (37, 41) or becomes degraded
(23). The Sp1-HDAC1 complex keeps the promoter inactive
until, in mid-G1, E2F1, -2, and -3 are synthesized, which
can bind to the free E2F motif, thereby displacing HDAC1 from the C
terminus of Sp1. Notably, E2F1, -2, or -3 itself interacts with RB,
which again recruits HDAC1 or HDAC2, thus keeping the promoter inactive
until mid-G1, when the pocket protein is phosphorylated.
Pocket protein phosphorylation results in its removal from E2F and in
the activation of the promoter by the combined activities of Sp1 and
E2F. This model could explain the complete shutoff of the mouse TK
promoter in growth-arrested cells and would allow for a stepwise
reorganization of promoter occupancy during G1, culminating
in promoter activation at the G1/S border of the cell
cycle. The model is in agreement with recent reports on the regulation
of the DHFR-promoter (25, 36, 45, 51). Those studies
conclude that Sp1, in addition to E2F, plays an active role in the
growth control of the DHFR promoter, although they do not provide a
mechanism for such a role.
We thank J. Taplick, E. Ogris, S. Schuechner, K. Kuchler, M. Cotten, and W. Krek for useful discussions, K. Kuchler for the GST
antiserum, H. Nomura for the pSp1-luc reporter plasmids, G. Suske for
the Sp1 antiserum, and H. Khier for the affinity-purified HDAC1 antiserum.
This work was supported by the Austrian FWF (grants P11179-GEN and
P13068-GEN to C.S. and grants P10873-GEN and P13031-MOB to E.W.) and
the Austrian National Bank (grant 6123 to C.S.).
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Abstract
Introduction
